The present invention relates to an apparatus and method for separating ions, more particularly the present invention relates to an apparatus and method for separating ions based on the ion focusing principles of high field asymmetric waveform ion mobility spectrometry (FAIMS).
High sensitivity and amenability to miniaturization for field-portable applications have helped to make ion mobility spectrometry (IMS) an important technique for the detection of many compounds, including narcotics, explosives, and chemical warfare agents as described, for example, by G. Eiceman and Z. Karpas in their book entitled xe2x80x9cIon Mobility Spectrometryxe2x80x9d (CRC, Boca Raton, 1994). In IMS, gas-phase ion mobilities are determined using a drift tube with a constant electric field. Ions are gated into the drift tube and are subsequently separated in dependence upon differences in their drift velocity. The ion drift velocity is proportional to the electric field strength at low electric field strength, for example 200 V/cm, and the mobility, K, which is determined from experimentation, is independent of the applied electric field. Additionally, in IMS the ions travel through a bath gas that is at sufficiently high pressure such that the ions rapidly reach constant velocity when driven by the force of an electric field that is constant both in time and location. This is to be clearly distinguished from those techniques, most of which are related to mass spectrometry, in which the gas pressure is sufficiently low that, if under the influence of a constant electric field, the ions continue to accelerate.
E. A. Mason and E. W. McDaniel in their book entitled xe2x80x9cTransport Properties of Ions in Gasesxe2x80x9d (Wiley, New York, 1988) teach that at high electric field strength, for instance fields stronger than approximately 5,000 V/cm, the ion drift velocity is no longer directly proportional to the applied field, and K becomes dependent upon the applied electric field. At high electric field strength, K is better represented by Kh, a non-constant high field mobility term. The dependence of Kh on the applied electric field has been the basis for the development of high field asymmetric waveform ion mobility spectrometry (FAIMS), a tern used by the inventors throughout this disclosure, and also referred to as transverse field compensation ion mobility spectrometry, or field ion spectrometry. Ions are separated in FAIMS on the basis of a difference in the mobility of an ion at high field strength, Kh, relative to the mobility of the ion at low field strength, K. In other words, the ions are separated because of the compound dependent behavior of Kh as a function of the applied electric field strength. FAIMS offers a new tool for atmospheric pressure gas-phase ion studies since it is the change in ion mobility, and not the absolute ion mobility, that is being monitored.
The principles of operation of FAIMS using flat plate electrodes have been described by I. A. Buryakov, E. V. Krylov, E. G. Nazarov and U.Kh. Rasulev in a paper published in the International Journal of Mass Spectrometry and Ion Processes; volume 128 (1993), pp. 143-148, the contents of which are herein incorporated by reference. The mobility of a given ion under the influence of an electric field is expressed by: Kh=K(1+f(E)), where Kh is the mobility of an ion at high electrical field strength, K is the coefficient of ion mobility at low electric field strength and f(E) describes the functional dependence of the ion mobility on the electric field strength. Ions are classified into one of three broad categories on the basis of a change in ion mobility as a function of the strength of an applied electric field, specifically: the mobility of type A ions increases with increasing electric field strength; the mobility of type C ions decreases; and, the mobility of type B ions increases initially before decreasing at yet higher field strength. The separation of ions in FAIMS is based upon these changes in mobility at high electric field strength. Consider an ion, for example a type A ion, which is being carried by a gas stream between two spaced-apart parallel plate electrodes of a FAIMS device. The space between the plates defines an analyzer region in which the separation of ions occurs. The net motion of the ion between the plates-is the sum of a horizontal x-axis component due to the flowing stream of gas and a transverse y-axis component due to the electric field between the parallel plate electrodes. The term xe2x80x9cnet motionxe2x80x9d refers to the overall translation that the ion, for instance said type A ion, experiences, even when this translational motion has a more rapid oscillation superimposed upon it. Often, a first plate is maintained at ground potential while the second plate has an asymmetric waveform, V(t), applied to it. The asymmetric waveform V(t) is composed of a repeating pattern including a high voltage component, V1, lasting for a short period of time t2 and a lower voltage component, V2, of opposite polarity, lasting a longer period of time t1. The waveform is synthesized such that the integrated voltage-time product, and thus the field-time product, applied to the plate during each complete cycle of the waveform is zero, for instance V1 t2+V2 t1=0; for example +2000 V for 10 xcexcs followed by xe2x88x921000 V for 20 xcexcs. The peak voltage during the shorter, high voltage portion of the waveform is called the xe2x80x9cdispersion voltagexe2x80x9d or DV in this disclosure.
During the high voltage portion of the waveform, the electric field causes the ion to move with a transverse y-axis velocity component v1=KhEhigh, where Ehigh is the applied field, and Kh is the high field ion mobility under ambient electric field, pressure and temperature conditions. The distance traveled is d1=v1t2=KhEhight2, where t2 is the time period of the applied high voltage. During the longer duration, opposite polarity, low voltage portion of the asymmetric waveform, the y-axis velocity component of the ion is v2=KElow, where K is the low field ion mobility under ambient pressure and temperature conditions. The distance traveled is d2=v2t1=KElowt1. Since the asymmetric waveform ensures that (V1t2)+(V2t1)=0, the field-time products Ehight2 and Elowt1 are equal in magnitude. Thus, if Kh and K are identical, d1 and d2 are equal, and the ion is returned to its original position along the y-axis during the negative cycle of the waveform, as would be expected if both portions of the waveform were low voltage. If at Ehigh the mobility Kh greater than K, the ion experiences a net displacement from its original position relative to the y-axis. For example, positive ions of type A travel farther during the positive portion of the waveform, for instance d1 greater than d2, and the type A ion migrates away from the second plate. Similarly, positive ions of type C migrate towards the second plate.
If a positive ion of type A is migrating away from the second plate, a constant negative dc voltage can be applied to the second plate to reverse, or to xe2x80x9ccompensatexe2x80x9d for, this transverse drift. This dc voltage, called the xe2x80x9ccompensation voltagexe2x80x9d or CV in this disclosure, prevents the ion from migrating towards either the second or the first plate. If ions derived from two compounds respond differently to the applied high strength electric fields, the ratio of Kh to K may be different for each compound. Consequently, the magnitude of the CV necessary to prevent the drift of the ion toward either plate is also different for each compound. Thus, when a mixture including several species of ions is being analyzed by FAIMS, only one species of ion is selectively transmitted for a given combination of CV and DV. The remaining species of ions, for instance those ions that are other than selectively transmitted through FAIMS, drift towards one of the parallel plate electrodes of FAIMS and are neutralized. Of course, the speed at which the remaining species of ions move towards the electrodes of FAIMS depends upon the degree to which their high field mobility properties differ from those of the ions that are selectively transmitted under the prevailing conditions of CV and DV.
An instrument operating according to the FAIMS principle as described previously is an ion filter, capable of selective transmission of only those ions with the appropriate ratio of Kh to K. In one type of experiment using FAIMS devices, the applied CV is scanned with time, for instance the CV is slowly ramped or optionally the CV is stepped from one voltage to a next voltage, and a resulting intensity of transmitted ions is measured. In this way a CV spectrum showing the total ion current as a function of CV, is obtained. It is a significant limitation of early FAIMS devices, which used electrometer detectors, that the identity of peaks appearing in the CV spectrum are other than unambiguously confirmed solely on the basis of the CV of transmission of a species of ion. This limitation is due to the unpredictable, compound-specific dependence of Kh on the electric field strength. In other words, a peak in the CV spectrum is easily assigned to a compound erroneously, since there is no way to predict or even to estimate in advance, for example from the structure of an ion, where that ion should appear in a CV spectrum. In other words, additional information is necessary in order to improve the likelihood of assigning correctly each of the peaks in the CV spectrum. For example, subsequent mass spectrometric analysis of the selectively transmitted ions greatly improves the accuracy of peak assignments of the CV spectrum.
In U.S. Pat. No. 5,420,424 which issued on May 30, 1995, B. L. Carnahan and A. S. Tarassove disclose an improved FAIMS electrode geometry in which the flat plates that are used to separate the ions are replaced with concentric cylinders, the contents of which are herein incorporated by reference. The concentric cylinder design has several advantages, including higher sensitivity compared to the flat plate configuration, as was discussed by R. W. Purves, R. Guevremont, S. Day, C. W. Pipich, and M. S. Matyjaszczyk in a paper published in Reviews of Scientific Instruments; volume 69 (1998), pp 4094-4105. The higher sensitivity of the cylindrical FAIMS is due to a two-dimensional atmospheric pressure ion focusing effect that occurs in the analyzer region between the concentric cylindrical electrodes. When no electrical voltages are applied to the cylinders, the radial distribution of ions should be approximately uniform across the FAIMS analyzer. During application of DV and CV, however, the radial distribution of ions is not uniform across the annular space of the FAIMS analyzer region. Advantageously, with the application of an appropriate DV and CV for an ion of interest, those ions become focused into a band between the electrodes and the rate of loss of ions, as a result of collisions with the FAIMS electrodes, is reduced. The efficiency of transmission of the ions of interest through the analyzer region of FAIMS is thereby improved as a result of this two-dimensional ion focusing effect.
The focussing of ions by the use of asymmetric waveforms has been discussed above. For completeness, the behavior of those ions that are not focussed within the analyzer region of a cylindrical geometry FAIMS is described here, briefly. As discussed previously, those ions having high field ion mobility properties that are other than suitable for focussing under a given set of DV, CV and geometric conditions will drift toward one or another wall of the FAIMS device. The rapidity with which these ions move towards the wall depends on the degree to which their Kh/K ratio differs from that of the ion that is transmitted selectively under the prevailing conditions. At the very extreme, ions of completely the wrong property, for instance a type A ion versus a type C ion, are lost to the walls of the FAIMS device very rapidly.
The loss of ions in FAIMS devices should be considered one more way. If an ion of type A is focussed, for example at DV 2500 volts, CV xe2x88x9211 volts in a given geometry, it would seem reasonable to expect that the ion is also focussed if the polarity of DV and CV are reversed, for instance DV of xe2x88x922500 volts and CV of +11 volts. This, however, is not observed and in fact the reversal of polarity in this manner creates a mirror image effect of the ion-focussing behavior of FAIMS. The result of such polarity reversal is that the ions are not focussed, but rather are extremely rapidly rejected from the device,. The mirror image of a focussing valley, is a hill-shaped potential surface. The ions slide to the center of the bottom of a focussing potential valley (2 or 3-dimensions), but slide off of the top of a hill-shaped surface, and hit the wall of an electrode. This is the reason for the existence, in the cylindrical geometry FAIMS, of the independent xe2x80x9cmodesxe2x80x9d called 1 and 2. Such a FAIMS instrument is operated in one of four possible modes: P1, P2, N1, and N2. The xe2x80x9cPxe2x80x9d and xe2x80x9cNxe2x80x9d describe the ion polarity, positive (P) and negative (N). The waveform with positive DV, where DV describes the peak voltage of the high voltage portion of the asymmetric waveform yields spectra of type P1 and N2, whereas the reversed polarity negative DV, waveform yields P2 and N1. The discussion thus far has considered positive ions but, in general, the same principles apply to negative ions equally.
A further improvement to the cylindrical FAIMS design is realized by providing a curved surface terminus of the inner electrode. The curved surface terminus is continuous with the cylindrical shape of the inner electrode and is aligned co-axially with an ion-outlet orifice of the FAIMS analyzer region. The application of an asymmetric waveform to the inner electrode results in the normal ion-focussing behavior described above, except that the ion-focussing action extends around the generally spherically shaped terminus of the inner electrode. This means that the selectively transmitted ions cannot escape from the region around the terminus of the inner electrode. This only occurs if the voltages applied to the inner electrode are the appropriate combination of CV and DV as described in the discussion above relating to 2-dimensional focussing. If the CV and DV are suitable for the focussing of an ion in the FAIMS analyzer region, and the physical geometry of the inner surface of the outer electrode does not disturb this balance, the ions will collect within a three-dimensional region of space near the terminus. Several contradictory forces are acting on the ions in this region near the terminus of the inner electrode. The force of the carrier gas flow tends to influence the ion cloud to travel towards the ion-outlet orifice, which advantageously also prevents the trapped ions from migrating in a reverse direction, back towards the ionization source. Additionally, the ions that get too close to the inner electrode are pushed back away from the inner electrode, and those near the outer electrode migrate back towards the inner electrode, due to the focusing action of the applied electric fields. When all forces acting upon the ions are balanced, the ions are effectively captured in every direction, either by forces of the flowing gas, or by the focussing effect of the electric fields of the FAIMS mechanism. This is an example of a three-dimensional atmospheric pressure ion trap, as disclosed in a copending PCT application in the name of R. Guevremont and R. Purves, the contents of which are herein incorporated by reference.
Ion focusing and ion trapping requires electric fields that are other than constant in space, normally occurring in a geometrical configuration of FAIMS in which the electrodes are curved, and/or are not parallel to each other. For example, a non-constant in space electric field is created using electrodes that are cylinders or a part thereof; electrodes that are spheres or a part thereof; electrodes that are elliptical spheres or a part thereof; and, electrodes that are conical or a part thereof. Optionally, various combinations of these electrode shapes are used.
As discussed above, one previous limitation of the cylindrical FAIMS technology is that the identity of the peaks appearing in the CV spectra are not unambiguously confirmed due to the unpredictable changes in Kh at high electric field strengths. Thus, one way to extend the capability of instruments based on the FAIMS concept is to provide a way to determine the make-up of the CV spectra more accurately, such as by introducing ions from the FAIMS device into a mass spectrometer for mass-to-charge (m/z) analysis. Advantageously, the ion focusing property of cylindrical FAIMS devices acts to enhance the efficiency for transporting ions from the analyzer region of a FAIMS device into an external sampling orifice, for instance an inlet of a mass spectrometer. This improved efficiency of transporting ions into the inlet of the mass spectrometer is optionally maximized by using a 3-dimensional trapping version of FAIMS operated in nearly trapping conditions. Under near-trapping conditions, the ions that have accumulated in the three-dimensional region of space near the spherical terminus of the inner electrode are caused to leak from this region, being pulled by a flow of gas towards the ion-outlet orifice. The ions that leak out from this region do so as a narrow, approximately collimated beam, which is pulled by the gas flow through the ion-outlet orifice and into a small orifice leading into the vacuum system of a mass spectrometer.
Additionally, the resolution of a FAIMS device is defined in terms of the extent to which ions having similar mobility properties as a function of electric field strength are separated tinder a set of predetermined operating conditions. Thus, a high-resolution FAIMS device transmits selectively a relatively small range of different ion species having similar mobility properties, whereas a low-resolution FAIMS device transmits selectively a relatively large range of different ion species having similar mobility properties. The resolution of FAIMS in a cylindrical geometry FAIMS is compromised relative to the resolution in a parallel plate geometry FAIMS because the cylindrical geometry FAIMS has the capability of focusing ions. This focusing action means that ions of a wider range of mobility characteristics are simultaneously focused in the analyzer region of the cylindrical geometry FAIMS. A cylindrical geometry FAIMS with narrow electrodes has the strongest focusing action, but the lowest resolution for separation of ions. As the radii of curvature are increased, the focusing action becomes weaker, and the ability of FAIMS to simultaneously focus ions of similar high-field mobility characteristics is similarly decreased. This means that the resolution of FAIMS increases as the radii of the electrodes are increased, with parallel plate geometry FAIMS having the maximum attainable resolution.
Note that, while the above discussion refers to the ions as being xe2x80x9ccapturedxe2x80x9d or xe2x80x9ctrappedxe2x80x9d, in fact, the ions are subject to continuous xe2x80x98diffusionxe2x80x99. Diffusion always acts contrary to focussing and trapping. The ions always require an electrical, or gas flow force to reverse the process of diffusion. Thus, although the ions are focused into an imaginary cylindrical zone in space with almost zero thickness, or within a 3-dimensional ion trap, in reality it is well known that the ions are actually dispersed in the vicinity of this idealized zone in space because of diffusion. This is important, and should be recognized as a global feature superimposed upon all of the ion motions discussed in this disclosure. This means that, for example, a 3-dimensional ion trap actually has real spatial width, and ions continuously leak from the 3-dimensional ion trap, for several physical, and chemical reasons. Of course, the ions occupy a smaller physical region of space if the trapping potential well is deeper.
It is significant limitation of the prior art FAIMS device that, when operated in a mode for trapping ions within a 3-dimensional region of space, there is a finite loading of the trap that can be achieved. Ions in excess of the loading limit begin to spill out of the trapping fields and will be lost. This limitation of the prior art FAIMS device is particularly problematic in those cases when several ion species have appropriate mobility properties to be trapped during a same overlapping period of time. In other words, the number of analyte ions in the trap is smaller, due to the presence of trapped background ions, which reduces the instrument sensitivity and increases the detection limit of the analyte ions.
Of course, other apparatus for trapping ions are known in the prior art. For instance, one type of an ion trap mass spectrometer is an radio-frequency (rf) quadrupole ion trap (ITMS), a device operating at low pressure, with the capability of trapping ions for storage. This device is optionally used as a mass analyzer, by electrically causing the ions within the trap to successively, as a function of their mass-to-charge ratio (m/z), become unstable and be ejected from the trap. Despite the versatility of the ITMS, it also has a very significant limitation. Since the strength of the trapping forces inside the ITMS is limited, if the trap contains a large number of ions, the space-charge ionxe2x80x94ion repulsion forces will overcome the trapping action, and the ions will be lost. This limitation is most severe if a minor component is to be detected in the presence of large numbers of ions that are other than of particular interest. Other types of ion trap mass spectrometers include, but are not limited to Fourier Transform Ion Cyclotron Resonance (FT-ICR) mass spectrometers and Penning ion trap mass spectrometers.
In a typical experiment, the compounds of a sample are ionized inside of the ITMS using an electron beam ionizer, for example. Since this form of ionization is not compound selective, ions from many of the components of the sample are formed. If the sample is composed of some compounds in high concentration, and a compound of interest is at trace levels, then the ratio of the number of background ions relative to the analyte compound is very high. The space-charge effects in the ITMS are usually experimentally minimized by reducing the ionization time, and hence the total number of ions which must reside in the ITMS. Of course, this works very well, but unfortunately the ITMS suffers from a loss of sensitivity if this approach is used. If the ionization time is shortened the ratio of background ions to the analyte ions is not altered, but the numbers of both of these ions is simply reduced. The net result is that the signal for the compound of interest is decreased. Normally therefore, the detection limit for the compound of interest is increased as the number of the ions of interest decreases.
It would be advantageous to provide a method and an apparatus for selectively transmitting an analyte ion prior to their introduction into an ion trapping device, for example one of an ion trapping FAIMS and an ITMS. Advantageously, pre-separating the analyte ion from the background ions greatly increases the dynamic sensitivity range of ion trapping devices.
In order to overcome these and other limitations of the prior art, it is an object of the present invention to provide an apparatus for separating ions having a relatively increased sensitivity toward a predetermined analyte ion.
In order to overcome these and other limitations of the prior art, it is an object of the present invention to provide an apparatus for separating ions in which ions that are other than of interest are selectively rejected within a first analyzer region of a tandem arrangement including two analyzers.
In accordance with the invention there is provided a method for trapping ions comprising the steps of:
a) providing a first analyzer region defined by a space between first and second spaced apart electrodes, the first analyzer region being in communication with a first ion inlet and a first ion outlet, the first ion inlet for receiving ions for introduction into the first analyzer region, the first ion outlet for providing ions from the first analyzer region;
b) providing a first asymmetric waveform and a first direct-current compensation voltage, to at least one of the first and second electrodes, to form an electric field therebetween, the first asymmetric waveform for effecting a difference in net displacement between the ions in the time of one cycle of the applied first asymmetric waveform;
c) setting the first compensation voltage for effecting a first separation of the ions to selectively transmit a first subset of the ions within the first analyzer region;
d) providing ions to the first analyzer region;
e) coupling ions from the ion outlet of the first analyzer region to a second analyzer; and,
f) trapping the selectively transmitted second subset of the ions with the second analyzer to accumulate ions within a trapping region thereof.
In accordance with the invention there is provided an apparatus for trapping ions comprising:
a) a first analyzer comprising at least two spaced apart electrodes defining a first analyzer region therebetween;
b) an ion source for providing ions to the first analyzer region;
c) a voltage source for providing an asymmetric waveform and a direct-current compensation voltage to at least one of the two electrodes of the first analyzer, to form an electric field therebetween, the asymmetric waveform for in use effecting a difference in net displacement between the ions in the time of one cycle of the applied asymmetric waveform and the compensation voltage for, in use, effecting a first separation of the ions by selectively transmitting a first subset of the ions within the first analyzer region;
d) a second analyzer for trapping ions, the second analyzer comprising at least two spaced apart electrodes defining a second analyzer region therebetween, the second analyzer region in fluid communication with the first analyzer region for in use receiving ions from the first analyzer region; and,
e) a voltage source for providing at least a temporally varying voltage to at least one of the two electrodes of the second analyzer, to form an electric field therebetween, the electric field for in use trapping ions from the first subset of the ions within the second analyzer region;
wherein in use the ion source is operated for a longer continuous period of time relative to an operation of a same ion source interfaced to an apparatus having a single analyzer.